Palmitic Acid Activates c-Myc via Dual Palmitoylation-dependent Pathways to Promote Colon Cancer

Transcriptional factor c-Myc plays a crucial role in various types of cancer including colon cancer. c-Myc is hyperactivated during the tumorigenesis and malignant progression of colon cancer, but the mechanisms underlying this transcriptional activation remain largely unknown. Considering that colon cancer is constantly exposed to intestinal metabolites, we wonder whether they play a key role in c-Myc transcriptional activation. Here, we reveal that palmitic acid is essential for the transcriptional activation of c-Myc during both inflammation-driven tumorigenesis and tumor progression. Notably, c-Myc is activated by palmitic acid in dual palmitoylation-dependent pathways  “passive activation under palmitic acid exposure” and “proactive activation through palmitic acid uptake”. Finally, exploiting metabolic addiction to palmitic acid as a vulnerability, we propose a promising therapeutic strategy inhibiting palmitoyltransferase ZDHHC9 and fatty acid transporter FATP2 which exerts favorable therapeutic effects against colon cancer. Together, these findings not only uncover a crucial biological role of palmitic acid on c-Myc activation depending on palmitoylation at distinct stages of colon cancer, but also highlights targeting ZDHHC9 and FATP2 as a promising option for colon cancer treatment.